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Additional Menopause Learning Issues And Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 MENOPAUSE/CONTRACEPTION/DUB SECTIONS: “BASIC SCIENCE” LEARNING OBJECTIVES • Describe the structure and function of the female reproductive system • Describe how peptide hormones of the hypothalamus and pituitary regulate reproductive system structure and function • Describe how steroid hormones regulate reproductive system differentiation, structure and function • Describe the production of steroid hormones in the ovarian substructures and how steroid hormone production is regulated by hypothalamic and pituitary peptide hormones. Note the key biosynthetic steps and precursors, and how genetics, disease and drugs may influence biosynthetic processes. • Characterize variations in hypothalamic and pituitary hormone levels and steroid hormone levels during maturation, puberty, pregnancy, the climacteric phase and menopause. • Generally describe how genetic defects or reproductive tissue pathologies may influence contribute to menstrual disorders/menopause • Describe the biochemical events involved in estrogen receptor stimulation and expression of estrogenic activity. Describe the different estrogen receptor subtypes and their tissue localization. • Generally describe the modulatory roles of the estrogenic hormones in skin and skeletal tissue, cardiovascular pathology, CNS function, the gut and other estrogen- dependent tissues (breast) • Describe the causes, clinical presentation, laboratory assessment of various reproductive tract disorders. • Describe the consequences of estrogen deficiency on the organ systems of the body • Describe the relationship between reproductive tract disorders and common comorbid conditions that develop • Describe the various structural sub-classes of estrogenic hormone drugs and how structure influences pharmacologic activity, key pharmacokinetic properties and adverse reaction profiles. Describe the rationale for differences in properties based on structure. • Describe the different formulations for the various structural sub-classes of steroid hormone drugs. Describe the rationale for different formulations. • Compare the available therapeutic modalities for estrogen replacement therapy (ERT), hormone replacement therapy (HRT) and other steroid hormone therapies (see cases related materials) 1 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 OVERVIEW OF REPRODUCTIVE PHYSIOLOGY AND PATHOPHYSIOLOGY AND THE STEROID HORMONES I. INTRODUCTION: REVIEW OF PHYSIOLOGY AND PATHOPHYSIOLOGY A. Embryonic Sexual Differentiation: Physiology and Pathophysiology Coursework - Gonadal sex and testes versus ovary development - Induced phenotypes - Puberty and the gonadotropin-releasing hormones - Estrogen-Dependent Tissues B. Brief review of physiology: Physiology and Pathophysiology Coursework - Ovaries and Follicle structure: the role of granulosa cells, thecal cells - Uterus and endometrial lining: Menstrual bleeding - Uterine tubules AND Vagina C. Review of the Menstrual Cycle: - Regulation by hypothalamus, pituitary, ovary and uterus with liver (SBG) and adrenals and thyroid gland - Hypothalamus: GnRH - Pituitary: Gonadotrophs (FSH and LH) - Ovarian Responses: See Estrogen Biosynthesis Chapter - Maturation of the Oocytes: Ovulation and Atresia - Synthesis and Secretion of Steroid Hormones: Phases - Thecal Cells: Androgen production (LH-modulation) - Granulosa Cells: Estrogen production from Androgens (FSH) Progesterone production: FSH ->LH receptors - Ovulation - Luteal Phase: Formation of the Corpus Luteum (Follicle) -Estrogen and Progesterone production: Endometrial maturation - LH production declines (Progesterone feedback) - Peak estradiol (E2: 200-400 pg/mL) and estrone (E1: 170-200 pg/mL) during the late follicular phase, then decrease to 40-60 pg/mL (estradiol) and 40-60 pg/mL (estrone) to early follicular phase. In menopause average E2 and E1 concentrations are 5-20 pg/mL and 30-70 pg/mL, respectively. The change in E2/E1 profile is derived from peripheral (adipose) frmation of E1 from androstenedione: Pre-menopause: E2/E1 > 1 Menopause: E2/E1 < 1 - End of Menstrual Cycle: Absence of fertilization and Implantation - Fertilization and Implantation: Placenta and hCG Production (P production) - HCG: Independent of E and P levels 2 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 The following diagram illustrates the hormonal inter-relationships in the control of the female reproductive system (GF = Graafian folicle, CL = corpus luteum, LH = luteinising hormone, FSH = follicle stimulating hormone and GnRH (LHRH) = gonadotrophin- releasing hormone). 3 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 D. Pregnancy: E. Lactation: F. Menopause 1. Natural History and Diminished Reproductive Function - Climacteric Phase: LH/FSH Levels, E, P and A levels and follicle and tissue development: FSH as a diagnostic marker - Change in steroid biosynthesis and level profiles (peripheral tissues) - Vasomotor symptoms: hot flashes, sweating and chills; - Psychologic/Mental status - Delayed systemic changes: Osteoporosis, CV, Skin, etc. G. Reproductive Tract Disorders: Tissue-based classification 1. Disorders of Sexual Differentiation: - Turner’s Syndrome: - Gonadal Dysgenesis: - Pseudohermaphroditism 2. Disorders of hypothalamic and Pituitary Function 3. Disorders of the Ovary 4. Disorders of the Uterus and Uterine Tubes and Vagina 5. Disorders of Pregnancy 6. Disorders of the Breast H. Menstrual Disorders: 1. Amenorrhea - Etiology: Normal versus pathologic (structural/functional disorders above) - Pathology and Pathogenesis: - Uterine Disorders: Curettage - Ovarian Failure: - Genetic Based: Turner’s Syndrome and mosaicism - Premature Ovarian Failure: Causes - Chronic Anovulation: - Hormonal Feedback Disorders: Polycystic ovary syndrome - Pituitary and Hypothalamic Disorders: Trauma, Sheehan’s Syndrome - Others: Anorexia nervosa, Stress, Hypothyroidism, hyperprolactinemia: - Clinical Manifestations: (KBL Notes/Cases) 2. Dysmenorrhea (Pain) 3. Menorrhagia (heavy menses) 4. Metrorrhagia (longer duration) I. Infertility: J. Preeclampsia-Eclampsia: 4 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 II. STEROID HORMONE OVERVIEW: SEE CHAPTER A. General Structure and Nomenclature B. Stereoisomerism: Role in ER binding C. Overview of Steroid Hormone Biosynthesis D. Overview of Steroid Hormone Receptor Actions E. Overview of Steroid Hormone Structural Alterations III. ESTROGENIC HORMONES AND ESTROGENIC DRUGS A. Introduction: The sex hormones, those endocrine substances involved in reproduction, the menstrual cycle and in giving women and men their characteristic physical differences, are all steroid in nature, While estrogens and progesterone are usually termed female sex hormones and testosterone is called a male sex hormone, it is important to note that all these steroids are biosynthesized in both males and females. B. Estrogen Biosynthesis: See Figure on Next Page • Cholesterol (C): Storage and biosynthesis in response to gonadotrophs • Biosynthetic Sites and Enzymes: Many, including aromatase, are CYP 450s Thecal cells: Cholesterol ->Androgens (testosterone) Granulosa Cells Androgens (testosterone) -> Estrogens (Estradiol) Corpus Luteum: Progesterone and Estrogens Androstenedione -> Testosterone ->Estradiol (reproductive) Androstenedione -> Estrone (peripheral tissues) • Aromatase: Both Androstenedione and Testosterone are substrates (An>T): • Variation with physiologic state: i.e. In pregnancy placenta main organ of E production • Other sites: Testes, adrenal cortex, hypothalamus and pituitary, adipose tissues (major site of estrogen production in post-menopausal women) • The major endogenous estrogens include 17ß-estradiol, estrone and estriol. 17ß-Estradiol is present in highest levels and is most active as an estrogen; estrone is about one-third as active as estradiol and estriol is about one-sixteenth as active. (Estradiol > Estrone > Estriol). 5 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 Biosynthesis of the Estrogens OR CH3 HO HO CH3 Aromatase Aromatase HO NADPH O2 NADPH O2 O O O Testosterone/Androstenedione H O H2O O Aromatase NADPH O2 H Enz O O H H O HO O HO HO OR OR O O O H H O Tautomerism CH3 R HO Estradiol (R=OH and H) or Estrone (R = O) 6 Drs DeRuiter, Braxton-Lloyd and Breese, Endocrine Module, Spring 2002 C. Receptor Actions: 1. Steroid Receptors and Actions: Estrogens versus other Steroid Hormones • Transport to site: Steroid Binding Proteins • Diffusion across the cell membrane • Stereospecific binding (17β-) to receptors in nucleus: A, E and Ps in nucleus, Gs in cytosol • Conformation change in receptor allowing for dimer formation • Dimeric complexes intereact with Hormone responsive elements (HREs) of DNA • Stimulation of Transcription -> mRNA (response time) • mRNA -> Protein synthesis in ER P receptors, etc.) • Compare receptors and HREs for various steroids (Gs, As, Es and Ps) 2. Estrogen Receptors: • Estrogen receptor affinity does not necessarily correlate with biologic potency (see Table) • Subtypes ER-beta and ER-alpha: • DNA binding domains (97% homologous) and Ligand binding domains (40% heterogeneity). 3. Differences in estrogenic activity of different estrogen products: • Different affinities for ERs and different activities at ER-ligand complexes: compound may be an agonist at one receptor site and antagonist at another • Pharmacokinetic differences: rate, nature of metabolism • ER receptor variability (alpha vs
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